Letter to the editor: Is the intratumor steatosis a novel biomarker for predicting the efficacy of immunotherapy in hepatocellular carcinoma?
Authors: Binghua Li, Decai Yu
Journal: Hepatology (2022)

To the editor, We read with interest the article by Murai et al.[1] In this study, the authors performed multiomics analyses of nonviral hepatocellular carcinoma (HCC) and found that patients with steatotic HCC were susceptible to immunotherapy. We applaud the authors for performing this comprehensive study. However, concerns and suggestions regarding the study remain. First, the authors used three HCC classifications including Class I/II/III, immune class, and steatotic/nonsteatotic class. However, the comparison between Class I/II/III and the steatotic class was not discussed. Second, steatosis is characterized by the accumulation of intracytoplasmic triglycerides within cells.[2] The authors only took fatty acids into consideration. Indeed, most fatty acids in steatotic HCC were significantly reduced based on the lipidomics profiling. Because triglyceride is the major component of lipid droplets and it is reported that intracellular triglyceride formation controls T cell responses to lipotoxicity,[3] the mechanistic link between other lipid categories including triglyceride and the immune‐exhausted microenvironment in steatotic HCC merits further discussion. Third, half of the 30 patients with advanced HCC were hepatitis B virus/hepatitis C virus positive. A subgroup survival analysis in nonviral steatotic/nonsteatotic HCC is needed because the authors focused on nonviral HCC. Fourth, we noticed that progression‐free survival (PFS) was used as a primary endpoint to assess the efficacy of immunotherapy. However, steatotic HCC was associated with less aggressive characteristics, including smaller tumor size, more differentiated grade, less vascular invasion, and earlier tumor stage.[4] In fact, steatotic HCC showed less macrovascular invasion and less extrahepatic metastasis than nonsteatotic HCC in this study, although it is not statistically significant, probably due to the limited sample size. Furthermore, we retrospectively analyzed the relationship between steatotic class and prognosis using The Cancer Genome Atlas (TCGA) dataset. Longer PFS time in steatotic HCC was observed than that in nonsteatotic HCC, whereas there is no significant difference in overall survival (Figure 1). Thus, the difference in tumor biological behavior may act as a confounder for therapeutic response and potentially result in overly optimistic conclusions. It would be more convincing if the authors could use the objective response rate as the primary efficacy endpoint for immunotherapy.FIGURE 1: Kaplan–Meier curves for progression‐free survival (PFS) (A) and overall survival (OS) (B) stratified by steatotic and nonsteatotic subtypes based on The Cancer Genome Atlas–Liver Hepatocellular Carcinoma (TCGA‐LIHC) dataset.Finally, although the authors have uploaded the multiomic datasets, the detailed clinical data were not provided. We think the authors should provide the de‐identified patient data so that the readers could repeat the results or re‐analyze the dataset. In conclusion, we believe that clarifications of the aforementioned questions would solidify the relationship between intratumor steatosis and immunotherapy response. AUTHOR CONTRIBUTIONS Binghua Li and Decai Yu conceived the manuscript. All authors reviewed the manuscript. CONFLICT OF INTEREST Nothing to report.